Deregulation of MYC plays an essential role in T cell acute lymphoblastic leukemia (T-ALL), yet the mechanisms underlying its deregulation remain elusive. Herein, we identify a molecular mechanism responsible for reciprocal activation between Aurora B kinase (AURKB) and MYC. AURKB directly phosphorylates MYC at serine 67, counteracting GSK3β-directed threonine 58 phosphorylation and subsequent FBXW7-mediated proteasomal degradation. Stabilized MYC, in concert with T cell acute lymphoblastic leukemia 1 (TAL1), directly activates AURKB transcription, constituting a positive feedforward loop that reinforces MYC-regulated oncogenic programs. Therefore, inhibitors of AURKB induce prominent MYC degradation concomitant with robust leukemia cell death. These findings reveal an AURKB-MYC regulatory circuit that underlies T cell leukemogenesis, and provide a rationale for therapeutic targeting of oncogenic MYC via AURKB inhibition.

中文翻译：

---

Aurora B 激酶直接磷酸化和稳定 MYC，促进 T 细胞白血病发生。

MYC 的失调在 T 细胞急性淋巴细胞白血病 (T-ALL) 中发挥着重要作用，但其失调的机制仍然难以捉摸。在此，我们确定了极光 B 激酶 (AURKB) 和 MYC 之间相互激活的分子机制。AURKB 直接磷酸化 MYC 的丝氨酸 67，抵消 GSK3β 引导的苏氨酸 58 磷酸化和随后的 FBXW7 介导的蛋白酶体降解。稳定的 MYC 与 T 细胞急性淋巴细胞白血病 1 (TAL1) 协同作用，直接激活 AURKB 转录，构成正前馈环，增强 MYC 调节的致癌程序。因此，AURKB 抑制剂会诱导显着的 MYC 降解，并伴有剧烈的白血病细胞死亡。这些发现揭示了 T 细胞白血病发生的 AURKB-MYC 调节回路，并为通过抑制 AURKB 靶向治疗致癌 MYC 提供了理论基础。